This proposal will continue our studies on the role of known and unknown mineralocorticoids in low renin hypertension (LRH). We have found that 25% of patients with LRH have unexplained bioassayable mineralocorticoid activity in the urine. We designed and have utilized an aldosterone radioreceptor assay to isolate a new mineralocorticoid, 19-nor-DOC, from the urine of rats with adrenal regeneration hypertension. We propose to show whether or not this steroid is produced in the human and, if so, to develop a radioimmunoassay to study its role, if any, in human hypertension. We have detected three areas of unknown radioreceptor activity in the urine of patients with LRH by using TLC of a urinary extract in combination with RIA of known mineralocorticoids and aldosterone radioreceptor assay. The urine of patients who are overproducing these steroids is being pooled and extracted. We plan to progressively purify these pooled extracts, as was done for 19-nor-DOC to identify those steroids which are contributing unknown radio-receptor activity. We will then evaluate the role of this steroid(s) in human hypertension. A significant proportion of patients with hypertension have some abnormalities in aldosterone regulation and/or metabolism. We have developed a radioimmunoassay for the main hepatic metabolite of aldosterone, tetrahydroaldosterone (THA). This metabolite will provide a better index of aldosterone secretion than the commonly used aldosterone 18-oxo-glucuronide (renal metabolite). We will measure THA in 4-hr urine and plasma samples with supine and upright posture during normal and sodium-depleted diet to study possible hepatic abnormalities of aldosterone metabolism in hypertensive patients. Preliminary studies show that the levels of plasma THA are 2-5 fold that of aldosterone; thus, it could be more useful for the diagnosis of primary aldosteronism or for studying the role of aldosterone in essential hypertension. The measurements of other known mineralocorticoids (DOC, 18-OH-DOC) with measurements of other, by then identified, steroids will give us an holistic view of the role of mineralocorticoids in LRH.